This is an application for a mentored Patient-Oriented Research Career Development Award (K23). The candidate is a psychiatrist who proposes to acquire the specific skills and knowledge necessary to become an independent investigator and leader in the field of psychiatric neuroimaging. Huntington's Disease (HD) is a prototypic neuropsychiatric illness with prominent psychiatric and cognitive dysfunction, a known genetic abnormality and consistent structural pathology. The candidate will be guided by known cognitive dysfunction to investigate, using functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI), the relationship between structure and function in early HD and in pre-symptomatic carriers of the HD genetic mutation. Career development activities will emphasize an integrative approach and focus on research methodology and statistics, cognitive neuropsychology, and functional and diffusion tensor neuroimaging acquisition and analysis techniques. The candidate plans to acquire skills through the study of HD that will generalize to the study of other neuropsychiatric conditions like schizophrenia . The research plan will focus on subjects in the early stages of HD and on pre-symptomatic HD mutation-positive individuals. Subjects will be recruited through the Johns Hopkins Department of Psychiatry Huntington's Disease Research Center, where they will have undergone rigorous clinical and cognitive evaluations. Specific Aim 1 will focus on fMRI analysis of hemodynamic activation during cognitive tasks designed to activate fronto-striatal circuits. Specific Aim 2 will use DTI data to study changes of fronto-striatal fractional anisotropy (FA), and Specific Aim 3 will investigate the relationships among clinical features, hemodynamic activation patterns and white matter changes. Future directions include the extension of this approach to patients with schizophrenia and other neuropsychiatric conditions in which cognitive symptoms manifest early and are refractory to current interventions. By working to understand the biology that subserves these cognitive processes we can approach thoughtful strategies for intervention and perhaps cure. RELEVANCE: Cognitive dysfunction is common among patients with neuropsychiatric disorders. By better understanding the biologic nature of this dysfunction, specific interventions may be developed to ease disease burden to patients, caregivers and society as a whole. [unreadable] [unreadable] [unreadable]